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Hyperplasia and impaired involution in the mammary gland of transgenic mice expressing human FGF4

Oncogene volume 19, pages 6007–6014 (2000)Cite this article

Abstract

Fgf4, a member of the fibroblast growth factor family, is frequently amplified in a variety of human cancers, however, its expression in neoplastic tissues is rarely detectable. This makes uncertain its involvement in tumour aetiology, although several in-vitro studies link Fgf4 overexpression to malignant transformation and metastatization of culture cells. We generated a transgenic mouse model in which the whey acidic protein (WAP) promoter directs expression of human Fgf4 to mammary tissues during late pregnancy and throughout lactation, with the purpose of studying the involvement of this growth factor in mammary tumorigenesis. Expression of the transgene was specifically detected in lobular-alveolar cells of lactating mammary glands that, by histological analysis, displayed hyperplastic areas and a disorganized structure. This was accompanied by an increased number of red blood cells and expression, in alveolar epithelial cells, of the vascular endothelial growth factor, which is absent in wild type controls. The most striking effect caused by FGF4 overexpression was on the remodelling of mammary tissue at the end of lactation. Indeed, transgenic animals showed a delayed involution of the gland due to a dramatic reduction in the overall number of apoptotic cells, which are normally present in the organ after weaning. Nevertheless, none of the animals examined developed neoplastic lesions of the mammary gland even after several pregnancies and at old age. Our work represents the first in-vivo demonstration of the anti-apoptotic and angiogenic properties of FGF4.

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Acknowledgements

We thank Prof Claudio Basilico for the FGF4 cDNA and antibody and for helpful advice and encouragement. We are also grateful to Prof Jeffrey Rosen for the generous gift of the WAP probe and for critically reading the manuscript. CNR ‘Progetto finalizzato ACRO’ and COFIN MURST supported this work.

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Author notes

  1. Monica Morini and Simonetta Astigiano: M Morini and S Astigiano contributed equally to the work in this paper.

Authors and Affiliations

  1. Unità Transgenici, Istituto Nazionale per la Ricerca sul Cancro, Largo R. Benzi 10, Genova, 16132, Italy

    Monica Morini, Simonetta Astigiano & Cristina Ricotta

  2. Servizio di Biologia Molecolare, Istituto Nazionale per la Ricerca sul Cancro, Largo R. Benzi 10, Genova, 16132, Italy

    Nicoletta Ferrari

  3. Unità di Morfogenesi Molecolare, Istituto Nazionale per la Ricerca sul Cancro, Largo R. Benzi 10, Genova, 16132, Italy

    Stefano Mantero & Giovanni Levi

  4. Iris, Chiron SpA., Siena, Italy

    Marirosa Mora

  5. Laboratoire de Physiologie Générale et Comparée, MNHN, Paris, URA CNRS 8572, France

    Giovanni Levi

  6. Dipartimento di Fisiopatologia e Medicina Sperimentale, Università di Siena, Italy

    Mara Rossini

  7. Dipartimento di Oncologia Biologia e Genetica, Università di Genova, Largo R. Benzi 10, Genova, 16132, Italy

    Ottavia Barbieri

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  1. Monica Morini
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Morini, M., Astigiano, S., Mora, M. et al. Hyperplasia and impaired involution in the mammary gland of transgenic mice expressing human FGF4. Oncogene 19, 6007–6014 (2000). https://doi.org/10.1038/sj.onc.1204011

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  • DOI: https://doi.org/10.1038/sj.onc.1204011

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